Bifunctional Compounds for the Treatment of COPD

Phillips, Gary B.; Salmon, M

doi:10.1016/b978-0-12-396492-2.00014-x

Cited by 12 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, bifunctional compounds in which a PDE4 inhibitor is connected to a muscarinic receptor antagonist have been described [70]. All use a pyrazolopyridine as the PDE4 inhibitor and a biaryl-containing muscarinic antagonist, but differ in the linker [71]. Another molecule with such dual activity is UCB-101333-3, a 4,6-diaminopyrimidine [72].…”

Section: Bifunctional Bronchodilator/anti-inflammatory Drugsmentioning

confidence: 99%

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Page

Cazzola

2014

Eur Respir J

View full text Add to dashboard Cite

Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting b 2 -agonist and an inhaled corticosteroid, and combinations of long-acting b 2 -agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of ''triple-inhaler'' fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called ''bifunctional drugs''. In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/antiinflammatory drugs and bifunctional anti-inflammatory drugs. @ERSpublications Bifunctional drugs offer an exciting new approach to the treatment of asthma and COPD

show abstract

Section: Bifunctional Bronchodilator/anti-inflammatory Drugsmentioning

confidence: 99%

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Page

Cazzola

2014

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…For the combination of a b 2 agonist and a PDE4 inhibitor, where both act through modulation of cAMP, there is an opportunity to provide additive or synergistic interactions, as has been previously reported (Seldon et al, 2005;Tannheimer et al, 2012a,b). This could be further enhanced, as a bifunctional molecule with a balanced optimal pharmacology could be delivered throughout the lung microenvironment, maintaining the ratio of interaction at the targets to provide maximal opportunity for their molecular interactions (Phillips and Salmon, 2012). It should be acknowledged, however, that from our current understanding of compartmentalized cAMP signaling, any cooperative interactions between a b 2 -adrenoceptor agonist and a PDE4 inhibitor could be cell type-and compartment-specific and that they may also act independently in many settings (Houslay, 2010).…”

Section: Compoundmentioning

confidence: 99%

“…Attempts to develop an inhaled PDE4 inhibitor have resulted in molecules with an improved side effect profile, while still being selective and potent (Chapman et al, 2010;Nials et al, 2011;TralauStewart et al, 2011). The combination of a bronchodilator with an anti-inflammatory agent as a treatment of COPD has been extensively discussed and is reviewed in Phillips and Salmon (2012). The ability of b 2 -adrenoceptor agonists to also have direct anti-inflammatory activity has been previously described, including inhibition of histamine, arachidonic acid metabolites, and TNFa release from mast cells (Undem et al, 1988;Bissonnette and Befus, 1997;Chong et al, 1998) and on cytokine release from monocytes (Seldon et al, 2005;Donnelly et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β₂-Adrenoceptor Agonist

Tannheimer

Sorensen

Cui

et al. 2014

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Inhaled long-acting b 2 -adrenoceptor agonists (LABA) that act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (, which has specific b 2 agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at b 2 adrenoceptors (EC 50 5 8 6 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC 50 5 5 6 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNFa) production in human peripheral mononuclear cells (PBMC) with an IC 50 5 0.3 nM [confidence interval (CI) 0.1-0.6] and in human neutrophils formyl-methionyl-leucyl-phenylalanine (fMLP)-induced super oxide anion production with an IC 50 5 3 nM . The addition of the b 2 antagonist ICI 118551 shifted the IC 50 in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both b 2 agonist and PDE4 inhibitory activity to GS-5759. GS-5759 was also a potent inhibitor of profibrotic and proinflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips precontracted with carbachol in a concentrationdependent manner with an EC 50 5 0.5 mM (CI 0.2-2) and had slow dissociation kinetics with an Off T 1/2 . 720 minutes at an EC 80 concentration of 3 mM. GS-5759 is a novel bifunctional molecule with both potent b 2 agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.

show abstract

“…An approach receiving considerable interest in respiratory medicine is the development of inhaled, bifunctional ligands. These new medicines contain two pharmacophores joined covalently at linker atoms by a pharmacologically inert "spacer" (Shonberg et al, 2011;Hughes et al, 2012;Phillips and Salmon, 2012). Bifunctional ligands have several advantages over the monofunctional parent compounds in combination.…”

Section: Introductionmentioning

confidence: 99%

“…Bifunctional ligands have several advantages over the monofunctional parent compounds in combination. Typically, their high molecular weight often translates into greater lung retention, low oral bioavailability, reduced systemic exposure, and an improved therapeutic ratio (Phillips and Salmon, 2012;Robinson et al, 2013). Moreover, the development of these compounds is simplified in terms of matched pharmacokinetics, formulation, and deposition characteristics (Shonberg et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

GS-5759, a Bifunctional β₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

Joshi

Dong

Hamed

et al. 2016

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

(R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl] carbamoyl}phenyl)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β-adrenoceptor agonist orthostere (β2A)] found in several β-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the K of GS-5759 for the β-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than β2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the β-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β-adrenoceptor agonism and PDE4 inhibition with potential to interact on target tissues in a synergistic manner. Such polypharmacological behavior may be particularly effective in chronic obstructive pulmonary disease and other complex disorders where multiple processes interact to promote disease pathogenesis and progression.

show abstract

Bifunctional Compounds for the Treatment of COPD

Cited by 12 publications

References 31 publications

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β₂-Adrenoceptor Agonist

GS-5759, a Bifunctional β₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

Contact Info

Product

Resources

About

Bifunctional Compounds for the Treatment of COPD

Cited by 12 publications

References 31 publications

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β2-Adrenoceptor Agonist

GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells

Contact Info

Product

Resources

About

The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β₂-Adrenoceptor Agonist

GS-5759, a Bifunctional β₂-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells